In mammals, embryo development and maintenance of adult homeostatsis depend on the establishment of a functional vascular system that supplies oxygen (O2) and other nutrients to the tissues and cells of the mammal Local oxygen delivery to these tissues and cells is regulated by the circulatory system through transient changes in the tone of pre-existing blood vessels, the establishment of new blood vessels (angiogenesis), and the remodeling of existing blood vessels to accept increased blood flow (arteriogenesis). Tissue perfusion under physiological and pathological conditions is regulated by hypoxia inducible factor-1 (HIF-1).
HIF-1 is a heterodimeric transcription factor composed of an oxygen-regulated alpha subunit (HIF-1α) and a constitutively expressed beta subunit (HIF-1β). HIF-1 mediates adaptive responses to hypoxia and ischemia in nucleated cells of metazoan organisms by directing transcription of genes involved in vascular homeostasis through effects on vascular tone, angiogenesis, and/or arteriogenesis. In pathological conditions, such as critical limb ischemia (CLI), HIF-1 can be inhibited, leading to decreased tissue perfusion, manifestation of ischemic pain at rest, ulceration, and/or gangrene, and eventually limb amputation.
Accordingly, a need exists for the identification and development of compositions and methods for treating disease associated with ischemia and/or hypoxia, including increasing tissue perfusion of the affected tissues and restoring normal physiological responses to ischemia and hypoxia.